Apolipoprotein E (apoE), a lipid transporting protein, is a major risk factor for developing Alzheimer's disease (AD). However, the contribution of apoE to nervous system function, and developing AD are unknown. One possible mechanism of apoE involvement in AD may be on the process involved with neuronal plasticity. Consistent with this proposed function, our in vitro studies have demonstrated that cortical neurons grown in medium containing apoE have significantly longer neurites than neurons grown in medium alone. We have paralleled these in vitro studies with in vivo studies. ApoE is expressed at high levels in the olfactory epithelium (OE), and olfactory bulb (OB) of mice. ApoE concentration increases several fold in the mouse OB following OE injury. Furthermore, olfactory nerve regeneration is significantly delayed in apoE-gene knockout (KO) mice as compared to wild-type (WT) littermates. While these findings suggest a critical role for apoE in olfactory receptor neuron (ORN) plasticity, the mechanism whereby apoE mediate these processes is unknown. In this proposal, we have advanced a series of experiments to identify the mechanism of apoE function in ORN plasticity. Aim 1 will test the hypothesis that apoE is important for cell proliferation in an injured OE. This hypothesis will be tested by using standard bromodeoxyuridine (BrdU) staining of OE in KO and WT littermates at several stages post OE lesioning induced by nasal irrigation of Triton X-100. Aim 2 will test the hypothesis that apoE facilitates ORN differentiation and maturation following OE lesioning. We will test this possibility by assessing the population of immature ORN (expressing growth associated protein 43, GAP-43) and mature ORN (expressing olfactory marker protein, OMP) in the OE of KO and WT mice by immunohistochemical and immunoblotting studies. Aim 3 will test the hypothesis that apoE promotes synaptogenesis of ORN with OB neurons post OE lesioning. This hypothesis will be tested by immunohistochemical analysis of synaptophysin (SYN, a synaptic marker) in the glomerular layer of KO and WT littermates following OE injury. The results from these studies will help clarify the role of apoE on ORN plasticity, and could potentially explain the association of apoE with AD.